In many developed and developing countries, the trend towards adoption of a diet containing high fat content and low fiber concentrations continues to be on the rise, accompanied by a labor-unintensive sedentary lifestyle. Such excessive intake of fat, accompanied by reduced conversion of fat into energy because of sedentary lifestyles can lead to accumulation of fat in the body at various levels including body fluids, cells and tissues. Consequently there is a steady rise in a population at a heightened risk of metabolic disorders such as overweight or obesity, which progresses to associated disorders like diabetes, cardiovascular disorders, metabolic syndrome, and hypertension.
In general the first line of treatment for individuals suffering from such metabolic disorders, in particular overweight or obesity, involves adoption of a diet low in fat and regular exercise. Compliance with such regimen however can be poor and, as the disease progresses, treatment with therapeutic drugs becomes necessary.
Accordingly, studies have been made towards developing drugs that are safe and effective for prevention and treatment of clinical manifestations that are caused as a consequence of accumulation of fat in body fluids, cells and tissues. Thus, there is a continuing necessity for decreasing the absorption and accumulation of fat in the body in some manner.
One approach to prevent or reduce fat accumulation is by reducing or inhibiting agents that aid in digestion and absorption of fat at various levels in the body. Enzymes belonging to the lipase gene family are of the central importance in lipid metabolism, absorption and transportation.
Hepatic lipase and lipoprotein lipase are multifunctional proteins which mediate the binding, uptake, catabolism, and remodeling of lipoproteins and phospholipids. Lipoprotein lipase and hepatic lipase function while bound to the luminal surface of endothelial cells in peripheral tissues and the liver respectively. Both enzymes participate in reverse cholesterol transport, which is the movement of cholesterol from peripheral tissues to the liver either for excretion from the body or for recycling. Genetic defects in both hepatic lipase and lipoprotein lipase are known to be the cause of familial disorders of lipoprotein metabolism. Defects in the metabolism of lipoproteins result in serious metabolic disorders, including hypercholesterolemia, hyperlipidemia, and atherosclerosis.
The lipase gene family enzymes are involved in a wide array of metabolic pathways, ranging from lipid digestion, absorption, fatty acid uptake, lipoprotein transportation and also in inflammation (Wong Howard et al., 2002, The lipase gene family, Journal of Lipid Research, Vol. 43: 993-999).
Pancreatic lipase is one of the key enzymes in lipid metabolism. It is synthesized by pancreatic acinar cells where it is secreted into the intestinal lumen and aids in the intestinal absorption of long chain triglyceride fatty acids (Verger, R. 1984, Pancreatic Lipases In Lipases. B. Borgström and H. L. Brockman, editors. Elsevier, New York. 83-150; Lowe, M. E. 1997, Molecular mechanisms of rat and human pancreatic triglyceride lipases. J. Nutr. 127: 549-557).
The action of the triacylglycerol lipases is believed to be antiatherogenic because these enzymes lower serum triacylglycerol levels and promote HDL formation. (Olivecrona, G., and Olivecrona, T. (1995) Curr. Opin. Lipid. 6:291-305). Lipoprotein lipase is the major enzyme responsible for the distribution and utilization of triglycerides in the body. Lipoprotein lipase hydrolyzes triglycerides in both chylomicrons and VLDL. Hepatic lipase hydrolyzes triglycerides in IDL and HDL, and is responsible for lipoprotein remodeling. Hepatic lipase also functions as a phospholipase, and hydrolyzes phospholipids in HDL.
Lipase members function in the metabolism of circulating lipoproteins. Hepatic lipase plays a role in the uptake of HDL cholesterol (Olivecrona, T., et al. 1993, Lipoprotein lipase and hepatic lipase. Curr. Opin. Lipidol. 4: 187-196). It is synthesized exclusively in the liver, where it is predominantly found (Hixenbaugh, E. A, et al., 1989, Hepatic lipase in the rat ovary. J. Biol. Chem. 264: 4222-4230).
A third member of the lipase gene family, lipoprotein lipase (LPL), is distributed in a variety of tissues, with the highest concentrations occurring in adipose tissue and muscle. This lipase is bound to capillary endothelium, where it functions to supply the underlying tissue with fatty acids derived from the triglyceride-rich core of circulating chylomicrons and VLDL (Olivecrona, T., and G. Bengtsson-Olivecrona. 1993. Lipoprotein lipase and hepatic lipase. Curr. Opin. Lipidol. 4: 187-196). In the process, LPL transforms these lipoproteins into remnant and HDL particles. Accumulating evidence suggest that LPL produced by macrophages in the vascular wall may facilitate the development of atherosclerosis by promoting lipid accumulation within the lesion. LPL has been shown to be involved in the pathogenesis of atherosclerosis (Mead J R, et al. 1999, “Lipoprotein Lipase, a key role in atherosclerosis?” FEBS Lett., November 26, 462(1-2): 1-6). Several groups have also proposed that both LPL and hepatic lipase besides their traditional role as lipolytic enzyme also appear to serve as ligands in the metabolism of plasma lipoproteins (Nykjaer, A., et al., 1993, The alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein binds lipoprotein lipase and beta-migrating very low density lipoprotein associated with the lipase. J. Biol. Chem. 268: 15048-15055; Krapp, A., S. et al., 1996. Hepatic lipase mediates the uptake of chylomicrons and VLDL into cells via the LDL receptor-related protein (LRP). J. Lipid Res. 37: 926-936). Transgenic animals expressing human lipoprotein lipase or hepatic lipase have decreased levels of plasma triglycerides and an increased level of high density lipoprotein (HDL) (Shimada, M., et al (1993) J. Biol. Chem. 268:17924-17929; Liu, M.-S., et al. (1994) J. Biol. Chem. 269:11417-11424).
A more recently discovered member of the lipase gene family is endothelial lipase. The function of this lipase is though uncertain at this time, it is believed to have a role in HDL metabolism (Jaye, M., et al., 1999, A novel endothelial-derived lipase that modulates HDL metabolism. Nat. Genet. 21: 424-428).
With the increasingly recognized potential of lipases in fat metabolism pathway, the drugs that inhibit or reduce the activity of lipases at various levels in the body form the front line of therapy for the treatment of diseases mediated by accumulation of fat at elevated levels.
A lipase inhibitor that is marketed as anti-obesity drug include Orlistat (XENICAL®) is described in U.S. Pat. No. 4,598,089. European Patent Application No. EP129748, relates to Orlistat and related compounds and their use in inhibiting pancreatic lipase and treating hyperlipidemia and obesity. Orlistat inhibits only intestinal lipases such as gastric, pancreatic and carboxylester lipases, particularly pancreatic lipase, in the gut lumen and blocks the digestion of dietary fat by preventing lipase from interacting with its lipid target. It however does not appear to have an effect on lipases other than the intestinal lipases, such as hepatic lipase or endothelial lipase, which are also recognized as having roles in catalyzing the hydrolysis of lipids. (Drent M L, van der Veen E A. Lipase inhibition: A novel concept in the treatment of obesity. Int J. Obes. Relat. Metab. Disord. 1993; 17:241-244.) Orlistat also tends to produce a high incidence of unpleasant (relatively harmless) side effects such as diarrhea.
Compounds that inhibit hepatic lipase and/or endothelial lipase activity have been disclosed in PCT Application No. WO2004094393 for the treatment of hepatic and/or endothelial lipase mediated diseases. The compounds are primarily directed towards increasing HDL levels by inhibiting the activity of hepatic and/or endothelial lipase, and are not intended to target intestinal or other lipases.
Therefore, it is desirable to develop new compounds that are useful in reducing or inhibiting metabolism, absorption, and accumulation of fat at various levels including fluids, cells, and tissues in the body by inhibiting or reducing the activity of all members of lipase gene family of interest and not just a particular type of lipase.
A plant benzoquinone embelin (2,5-dihydroxy-3-undecyl-1,4-benzoquinone) obtained from the dried fruit of Embelia ribes and known as an antifertility agent has also been reported to elevate activities of the lipogenic enzymes, malate dehydrogenase, glucose-6-phosphate dehydrogenase and hydroxymethylglutaryl-CoA reductase while essentially not affecting lipolytic enzyme activities. (Gupta S. et al., Fitoterapia 60(4):331-338 (1989).) Embelin is also used as ateniacide, as having antitumor, anti-inflammatory and analgesic properties (Chitra et al. Chemotherapy 40:109 (1994)) and as a cell-permeable, non-peptide inhibitor of X-linked inhibitor of apoptosis (XIAP). (Nikolovska-Coleska et al. J. Med. Chem. 47:2430 (2004)).